Review articleFamilial hypercholesterolemia treatments: Guidelines and new therapies
Introduction
Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high levels of circulating low density lipoprotein cholesterol (LDL-C) from birth. This does result in the fast development of atherosclerosis with detrimental outcomes such as myocardial infarction and death occurring early in life in patients with FH, especially in those who are not or inadequately treated [[1], [2], [3], [4]]. Despite several effective cholesterol-lowering drugs now being available, a main gap in the management of this disease is the lack of early detection and appropriate pharmacological intervention of FH subjects. In fact, the most severe forms, such as homozygous FH, generally exhibit unambiguous physical signs from the childhood; in contrast, less severe forms of FH may remain hidden until the occurrence of the first cardiovascular event. Thus, the early identification of these subjects is crucial to reduce the burden of cholesterol exposure and the incidence of cardiovascular events.
Genetic defects in several genes involved in LDL metabolism may cause FH; mutations in the LDLR gene, encoding for the LDL receptor (LDLR) are the most common cause of FH, but mutations in the APOB gene and gain-of-function (GOF) mutations in the PCSK9 gene can also result in the FH phenotype [[5], [6], [7]]. A rare recessive form of hypercholesterolemia (autosomal recessive hypercholesterolemia, ARH) is caused by the loss-of-function mutations in the LDLRAP1 gene (encoding for a protein that promotes the internalization of LDLR/LDL complex) [8,9]. However, among subjects with a clinical diagnosis of FH, only 40–80%, depending on the criteria used, exhibit a mutation in one of the classical genes causative of FH, which suggests that a relatively high proportion of “mutation-negative” FH patients are likely to have a polygenic cause underlying their marked hypercholesterolemia [10,11].
The heterozygous form of FH (HeFH) has a prevalence of ∼1/500 to 1/200 in the general population and is characterized by a 2–3 fold increase of LDL-C levels and the occurrence of coronary heart disease (CHD) before age 55 (60 for women) [1,2,12]; the homozygous form (HoFH) is rarer, with a prevalence of ∼1/160,000–1/300,000, and HoFH patients are generally characterized by an even more severe LDL-C level phenotype. This greater cholesterol burden does result in the onset of extremely premature cardiovascular disease, with HoFH patients who suffer from a myocardial infarction well before their 10th year of age [2], particularly in HoFH patients who carry two receptor-negative mutations [2,5]. Subjects carrying mutations in APOB or PCSK9 genes generally exhibit a milder phenotype [6,13].
The diagnosis of FH can be based either on clinical criteria or genetic testing; the last provides a definitive diagnosis of FH, but there are some patients with clinical diagnosis of FH in whom no mutation can be identified in the genes classically associated to this condition, suggesting the involvement of unknown genes or a polygenic cause. However, a positive genetic test allows one to discriminate a FH subject from a “normal” hypercholesterolemic individual on the one hand [14], and on the other aids in the identification of FH among relatives. Due to the high number of possible mutations causing FH and due to the possible involvement of additional genes, the phenotype of FH is highly variable, and subjects carrying the same mutation may exhibit profoundly different lipid and clinical profiles as well as different responses to the same pharmacological treatment; in addition, subjects with HoFH may present LDL-C levels well below those expected for this condition and thus may not be recognized.
Section snippets
Guidelines for the management of familial hypercholesterolemia
Based on a prevalence of 1/200-1/500, it can be estimated that there are between 14 and 34 million individuals having FH worldwide, but in most countries less than 1% are diagnosed (with some exceptions) [1]. Another major key point is that subjects with FH have an at least 10-fold increase risk of CHD, which may manifest early in life, and the risk remains high even among patients treated with statins, which suggests that they are treated with therapies that are inadequate (low dose, late in
Statins
Statin therapy represents the first pharmacological approach for the management of hypercholesterolemia in FH patients, and current guidelines recommend that adults are treated with the maximal tolerated dose of a high potency statin [1]. In most cases, however, statin monotherapy is insufficient to achieve the recommended LDL-C levels.
Given the mechanism of action of statins, which exert their lipid-lowering effect partly by increasing the hepatic expression of LDLR, it is expected that
Conclusions
Current guidelines strongly support treatment of FH with goals of 100 (2.56 mmol/L) and 70 mg/dL (1.86 mmol/L) according to the risk levels. Up to 3 decades ago, the treatment of severe hypercholesterolemia in FH was a clinical dilemma. The availability of statins and later on of other pharmacological interventions has produced a dramatic shift in our capability of controlling LDL levels even in homozygous patients, with a few exceptions in which apheresis is still required. The most important
Conflicts of interest
F.J.R. has received research grants from Amgen, Sanofi, Regeneron Pharmaceuticals, Inc. and the Medicines Company, has served on and received honoraria for a Speakers Bureau and consultant/advisory boards for Amgen, Sanofi, Regeneron Pharmaceuticals, Inc., and the Medicines Company.
G.K.H. reports consulting and/or lecture fees from Amgen Inc, Regeneron/Sanofi, and Pfizer related to PCSK9 inhibitors, and institutional research funding related to PCSK9 inhibitor clinical trials from Amgen Inc,
Financial support
The work of ALC is supported by: Fondazione Cariplo 2015-0524 and 2015-0564; H2020 REPROGRAM PHC-03-2015/667837-2; ERA-NET ER-2017-2364981.
References (110)
- et al.
The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies
J. Am. Coll. Cardiol.
(2014) - et al.
Familial defective apolipoprotein B-100: a review
J. Clin. Lipidol.
(2016) - et al.
The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification
Gene
(2015) - et al.
Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study
Lancet
(2013) - et al.
Familial hypercholesterolemia-epidemiology, diagnosis, and screening
Curr. Atherosclerosis Rep.
(2015) - et al.
Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation
Atherosclerosis
(2014) - et al.
Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia
J. Am. Coll. Cardiol.
(2016) - et al.
2016 ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)
Atherosclerosis
(2016) - et al.
Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia
Lancet
(2004) - et al.
Early statin therapy restores endothelial function in children with familial hypercholesterolemia
J. Am. Coll. Cardiol.
(2002)
Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review
Atherosclerosis
Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia
Atherosclerosis
Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia
Atherosclerosis
Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia
Atherosclerosis
A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia
Atherosclerosis
Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: results from the CHARON study
J. Clin. Lipidol.
Efficacy of rosuvastatin in children with homozygous familial hypercholesterolemia and association with underlying genetic mutations
J. Am. Coll. Cardiol.
Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality
J. Am. Coll. Cardiol.
Cardiovascular risk in patients with familial hypercholesterolemia using optimal lipid-lowering therapy
J. Clin. Lipidol.
Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation
J. Am. Coll. Cardiol.
Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia
Atherosclerosis
Pleiotropic effects of ezetimibe: do they really exist?
Eur. J. Pharmacol.
Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial
J. Am. Coll. Cardiol.
Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia
J. Am. Coll. Cardiol.
PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses
J. Am. Coll. Cardiol.
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
Lancet
Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial
Lancet
Long-term treatment with evolocumab homozygous familial hypercholesterolemia patients: results from the trial assessing long-term use of PCSK9 inhibition in subjects with genetic LDL disorders (TAUSSIG)
Atherosclerosis
Cardiovascular event rates in homozygous familial hypercholesterolemia (HOFH): trialassessing long-term use of pcsk9 inhibition in subjects with genetic LDL disorders (TAUSSIG) study interim results
Atherosclerosis
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial
Lancet
Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia
Am. J. Cardiol.
Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials
J. Clin. Lipidol.
Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia
J. Lipid Res.
Liver histology during Mipomersen therapy for severe hypercholesterolemia
J. Clin. Lipidol.
New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes
Clin. Therapeut.
Emerging LDL therapies: mipomersen-antisense oligonucleotide therapy in the management of hypercholesterolemia
J. Clin. Lipidol.
Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia
J. Clin. Lipidol.
Emerging low-density lipoprotein therapies: microsomal triglyceride transfer protein inhibitors
J. Clin. Lipidol.
Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: the Italian cohort
Nutr. Metabol. Cardiovasc. Dis. : Nutr. Metabol. Cardiovasc. Dis.
Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study
Lancet
LOWER, a registry of lomitapide-treated patients with homozygous familial hypercholesterolemia: rationale and design
J. Clin. Lipidol.
JCL roundtable: risk evaluation and mitigation strategy
J. Clin. Lipidol.
ANGPTL3 deficiency and protection against coronary artery disease
J. Am. Coll. Cardiol.
Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion
J. Lipid Res.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society
Eur. Heart J.
Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society
Eur. Heart J.
Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment
Eur. Heart J.
Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death
Eur. Heart J.
Lipid disorders and mutations in the APOB gene
Clin. Chem.
Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein
Science
Cited by (120)
SEA 2024 Standards for Global Control of Vascular Risk
2024, Clinica e Investigacion en ArteriosclerosisRecent advances in the management and implementation of care for familial hypercholesterolaemia
2023, Pharmacological ResearchA Bibliometric Analysis of Familial Hypercholesterolemia From 2011 to 2021
2023, Current Problems in CardiologyHomozygous Familial Hypercholesterolemia in Canada: An Observational Study
2023, JACC: Advances